Ache, cutaneous infections, psoriasis and other disorders of the cutaneous and pilosebaceous unit or the process of keratogenesis are typically characterized by the presence of visible dermatological lesions, such as the raised closed comedones, the often colored open comedones, red or pustular-looking inflamed papules, pustules, nodules and cysts of acne or cutaneous infection; the readily visible ingrown hairs of pseudofolliculitis barbae; or the visible scales of seborrhea, ichthyosis and psoriasis. Clinical evaluation of potential treatments for such disorders is typically based on the effectiveness of the treatment in reducing the number and severity of these visible lesions.
Prior to the eruption of visible lesions on the surface of the skin, non-visible lesions, herein referred to as pre-emergent lesions, are generally present within the skin. While pre-emergent lesions are insufficiently visible to be graded in conventional clinical studies, their presence within the skin can be discerned by the tactile sense of feel and/or by pain and tension within the skin.
Pre-emergent lesions are caused by a pre-emergent process within the epidermis and dermis, or within and surrounding the pilosebaceous follicle, which is located within the skin's epidermis, dermis, or both. In acne, for example, this pre-emergent process usually begins within the pilosebaceous follicle. The pilosebaceous follicle is filled with sebum secreted into the follicle by the sebaceous gland, bacteria, (primarily corynebacterium acnes, or P. aches) and keratin cells which slough off the inner wall of the follicle. In the pre-emergent process, the follicular wall is attacked by inflammatory agents, in particular excess free fatty acids produced by the breakdown of triglycerides present in the sebum by lipolytic enzymes, or lipases, and chemotactic and inflammatory agents that are produced and induced from P. acnes. Research has shown that, compared to normal patients, acne patients have increased levels of sebum secretion and increased presence of P. acnes and its associated lipase activity, with a resulting increase in the level of free fatty acids and other associated inflammatory agents. These increases have been shown to be roughly proportional to the severity of the disorder.
In addition, acne patients often have abnormal follicular walls. In normal skin, the follicular wall is composed entirely of keratinized cells, formed by the process of keratinization. This keratinized cell wall forms a barrier between the sloughed keratin cells, and the sebaceous and bacterial components within the follicle and the aqueous tissue surrounding the follicle. In ache patients, faulty keratinization apparently allows structurally weaker sebum-containing cells to be inserted into the follicular wall, thereby making the wall more vulnerable to attack and rupture. Once the cell wall is breached, free fatty acids, sebaceous and inflammatory components, live and dead bacteria, sloughed cells from the follicular wall and other follicle contents are released into the aqueous tissue surrounding the follicle, where they establish an inflammatory process (Webster, G., Jnl. Am. Acad. Dermatol., 1955; 33:247-253).
The pre-emergent process described above can progress to the point where, though not visible on the surface, the inflammation and resulting internal lesions can be felt within the skin as a sensation or as pain, and may also be felt by touch on the surface of the skin as a bump.
While several studies have been published on the individual effects of agents such as benzoyl peroxide, alpha hydroxy acids and zinc agents on dermatological problems visible on the surface of the skin, such as non-inflamed comedones, inflamed papules and pustules, cutaneous infections, ingrown hairs, and keratotic scales (Handbook of Non-Prescription Drugs, American Pharmaceutical Association, 9th Ed. (1990) 798; Goodman and Gilman, Pharmacologic Basis of Therapeutics, MacMillan Publishing Co., 6th Ed. (1980), 977; Ruey, J. Y., Van Scott, E. J., U.S. Pat. No. 4,363,815), the inventors are unaware of any published reports of the efficacy of recognized acne drugs on pre-emergent lesions.